(556a) Topical Anesthesia Achieved By Tetrodotoxin(TTX)-Filled Marker-Pen Delivery System

The skin pain can be neuropathic or nociceptive, and can be caused by several circumstances. The mainstream management strategy for skin pain is local anesthesia, including the utilization of infiltrated anesthetics and topical anesthetics. For severe pain, opioid medication is sometimes applied, which may result in multiple side effects or sequelae. Tetrodotoxin(TTX), as a representative of site 1 channel sodium blockers(S1SCBs), is now considered as a potent compound for local anesthesia, which may provide an alternative strategy for severe pain management. Nevertheless, the utilization of TTX faces two main obstacles. The first is that the permeation ability through the skin of TTX is limited due to the high hydrophilicity. Chemical permeation enhancers(CPEs) can be applied along with the TTX formula, the penetration performance was promoted 10 folds through the tympanic membrane; Besides, TTX has extreme systemic toxicity, the release of which should maintain under control, for which the marker-pen delivery system is developed to achieve zero-order release. In this study, the release performance and stability of the marker-pen delivery system were evaluated on both porcine and rat skin, and the average release mass of TTX from the marker pen with 0.4 mg mL^-1 formula was confirmed as 30 ng cm^-1. The enhancement evaluation by in vitro permeation test(IVPT) for CPE formula of 1% sodium dodecyl sulfate(SDS) and 2% limonene(LIM) was applied on both porcine whole skin and dermatomed skin, which showed that the permeated mass of TTX was elevated through dermatomed skin while no significant difference observed through whole skin. It confirmed that the CPE can increase the penetration of TTX through the epidermis while not making it enter the muscle and vascular environment to affect as systemic toxicity. In vivo analgesic effect evaluation was carried out with both single- and multiple-triggered. It is confirmed that an application of 900 ng TTX by the marker-pen delivery system (30 cm) can produce a sensory nerve blockade for 14 hours at maximum, with a threshold improvement of around 4 folds. As a contrast, the bupivacaine-filled marker pen was also assembled, with a concentration of 40 mg mL^-1. The 10 cm(2.8 µg) application of bupivacaine produced only 15 min(without CPE) to 30 min(with CPE) nerve blockade, with a threshold improvement of around 20%, which highlighted the effectiveness of TTX for functioning better anesthesia with a lower dose. The long-term multiple-triggered evaluation showed the TTX-filled marker-pen system maintained the anesthetic performance for 10 times in 10 days while no side effect was observed. In conclusion, the maker-pen delivery for TTX formula consisted with CPE provides an alternative strategy for severe skin pain management, by which the released mass, thereby the analgesic duration can be estimated by the length drawn on the skin.